Drug priming enhances radiosensitivity of adamantinomatous craniopharyngioma via downregulation of survivin

Stache, Christina; Bils, Christiane; Fahlbusch, Rudolf; Flitsch, Jörg; Buchfelder, Michael; Stefanits, Harald; Czech, Thomas; Gaipl, Udo S.; Frey, Benjamin; Buslei, Rolf; Hölsken, Annett

doi:10.3171/2016.9.focus16316

Cited by 13 publications

(11 citation statements)

References 69 publications

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“…Clinical data documents recurrence after radiotherapy in ACP patients . In vitro experiments support this notion, as radiation induced cell death is lower in primary ACP tumor cells where EGFR signaling is activated. This effect is maintained by the EGFR‐induced upregulation of the anti‐apoptotic protein survivin.…”

Section: Primary Cell Culture Modelmentioning

confidence: 87%

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Models of human adamantinomatous craniopharyngioma tissue: Steps toward an effective adjuvant treatment

Hölsken

Buslei

2017

Brain Pathology

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Even though ACP is a benign tumor, treatment is challenging because of the tumor's eloquent location. Today, with the exception of surgical intervention and irradiation, further treatment options are limited. However, ongoing molecular research in this field provides insights into the pathways involved in ACP pathogenesis and reveal a plethora of druggable targets. In the next step, appropriate models are essential to identify the most suitable and effective substances for clinical practice. Primary cell cultures in low passages provide a proper and rapid tool for initial drug potency testing. The patient-derived xenograft (PDX) model accommodates ACP complexity in that it shows respect to the preserved architecture and similar histological appearance to human tumors and therefore provides the most appropriate means for analyzing pharmacological efficacy. Nevertheless, further research is needed to understand in more detail the biological background of ACP pathogenesis, which provides the identification of the best targets in the hierarchy of signaling cascades. ACP models are also important for the continuous testing of new targeting drugs, to establish precision medicine.

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Section: Primary Cell Culture Modelmentioning

confidence: 87%

“…Notably, the inhibition of EGFR signaling significantly increases irradiation susceptibility and reveals that EGFR inhibitor potency varies considerably. CUDC‐100 targeting the EGFR was shown to be much more effective than the EGFR inhibitor Gefitinib .…”

Section: Primary Cell Culture Modelmentioning

confidence: 99%

Models of human adamantinomatous craniopharyngioma tissue: Steps toward an effective adjuvant treatment

Hölsken

Buslei

2017

Brain Pathology

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“…Here again, fractionated and hypofractionated RT were the main stimulus for increased PD‐L1 surface expression. The in vivo examinations are currently ongoing, since we are now able to locally irradiate orthotopic brain tumors …”

Section: Immunosuppression By Radiationmentioning

confidence: 99%

“…The in vivo examinations are currently ongoing, since we are now able to locally irradiate orthotopic brain tumors. 113,114 It has become obvious that besides T cell-derived IFNγ-induced expression of PD-L1, exogenous stimuli delivered by pathogen-associated molecular patterns, further cytokines and epidermal growth factor can induce surface expression of PD-L1 via multiple pathways. 115,116 With our in vitro experiments, hints were obtained that both, tumor cell-derived IFNγ and IL-6 might trigger PD-L1 expression.…”

Section: Radiation and Immune Checkpoint Moleculesmentioning

confidence: 99%

Immunomodulation by ionizing radiation—impact for design of radio‐immunotherapies and for treatment of inflammatory diseases

Frey

Rückert

Deloch

et al. 2017

Immunological Reviews

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Ionizing radiation is often regarded as an element of danger. But, danger responses on the cellular and molecular level are often beneficial with regard to the induction of anti-tumor immunity and for amelioration of inflammation. We outline how in dependence of radiation dose and fraction, radiation itself-and especially in combination with immune modulators-impacts on the innate and adaptive immune system. Focus is set on radiation-induced changes of the tumor cell phenotype and the cellular microenvironment including immunogenic cancer cell death. Mechanisms how anti-tumor immune responses are triggered by radiotherapy in combination with hyperthermia, inhibition of apoptosis, the adjuvant AnnexinA5, or vaccination with high hydrostatic pressure-killed autologous tumor cells are discussed. Building on this, feasible multimodal radio-immunotherapy concepts are reviewed including overcoming immune suppression by immune checkpoint inhibitors and by targeting TGF-β. Since radiation-induced tissue damage, inflammation, and anti-tumor immune responses are interconnected, the impact of lower doses of radiation on amelioration of inflammation is outlined. Closely meshed immune monitoring concepts based on the liquid biopsy blood are suggested for prognosis and prediction of cancer and non-cancer inflammatory diseases. Finally, challenges and visions for the design of cancer radio-immunotherapies and for treatment of benign inflammatory diseases are given.

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“…Although results are preliminary, they integrate the findings discussed above regarding pathologic EGFR activation, which is associated with radioresistance in other intracranial neoplasms including glioma, as well as with craniopharyngioma proliferation and recurrence, as discussed above. 29,[132][133][134][135][136] In vitro analysis demonstrated that human adamantinomatous craniopharyngioma cultures underwent significantly increased cell death when RT was preceded by tyrosine kinase inhibition using gefitinib or CUDC-101, a mechanism that was further shown to be mediated by downregulation of survivin, an established mediator of radioresistance. [135][136][137] Significant further research is required before this can be added to the clinical treatment armamentarium; notwithstanding, the optimistic preliminary results highlight a potential modality for dose minimization, enhanced local control, and decreased morbidity.…”

Section: Overview Of Radiotherapymentioning

confidence: 99%

Pediatric Craniopharyngiomas: A Primer for the Skull Base Surgeon

et al. 2018

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Pediatric craniopharyngioma is a rare sellar-region epithelial tumor that, in spite of its typically benign pathology, has the potential to be clinically devastating, and presents a host of formidable management challenges for the skull base surgeon. Strategies in craniopharyngioma care have been the cause of considerable controversy, with respect to both philosophical and technical issues. Key questions remain unresolved, and include optimizing extent-of-resection goals; the ideal radiation modality and its role as an alternative, adjuvant, or salvage treatment; appropriate indications for expanded endoscopic endonasal surgery as an alternative to transcranial microsurgery; risks and benefits of skull base techniques in a pediatric population; benefits of and indications for intracavitary therapies; and the preferred management of common treatment complications. Correspondingly, we sought to review the preceding basic science and clinical outcomes literature on pediatric craniopharyngioma, so as to synthesize overarching recommendations, highlight major points of evidence and their conflicts, and assemble a general algorithm for skull base surgeons to use in tailoring treatment plans to the individual patient, tumor, and clinical course. In general terms, we concluded that safe, maximal, hypothalamic-sparing resection provides very good tumor control while minimizing severe deficits. Endoscopic endonasal, intraventricular, and transcranial skull base technique all have clear roles in the armamentarium, alongside standard craniotomies; these roles frequently overlap, and may be further optimized by using the approaches in adaptive combinations. Where aggressive subtotal resection is achieved, patients should be closely followed, with radiation initiated at the time of progression or recurrence-ideally via proton beam therapy, although three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and stereotactic radiosurgery are very appropriate in a range of circumstances, governed by access, patient age, disease architecture, and character of the recurrence. Perhaps most importantly, outcomes appear to be optimized by consolidated, multidisciplinary care. As such, we recommend treatment in highly experienced centers wherever possible, and emphasize the importance of longitudinal follow-up-particularly given the high incidence of recurrences and complications in a benign disease that effects a young patient population at risk of severe morbidity from hypothalamic or pituitary injury in childhood.

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Drug priming enhances radiosensitivity of adamantinomatous craniopharyngioma via downregulation of survivin

Cited by 13 publications

References 69 publications

Models of human adamantinomatous craniopharyngioma tissue: Steps toward an effective adjuvant treatment

Models of human adamantinomatous craniopharyngioma tissue: Steps toward an effective adjuvant treatment

Immunomodulation by ionizing radiation—impact for design of radio‐immunotherapies and for treatment of inflammatory diseases

Pediatric Craniopharyngiomas: A Primer for the Skull Base Surgeon

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